This R01 proposal was written in response to PA-07-374, Psychopharmacology of widely available psychoactive natural products. The purpose of this proposal is to examine whether neuroplasticity of dopamine (DA) signaling in the nucleus accumbens (NAc) underlies the reward-altering effects of the psychotomimetic drug salvinorin A (salvA). Salvinorin A (SalvA) is the main active ingredient of the hallucinogenic plant Salvia divinorum and is a potent and selective kappa opioid receptor (KOR) agonist (Roth et al., 2002). Salvia is rapidly gaining in popularity among American youth as a drug of abuse, but little is known about the mechanisms through which salvA impacts brain reward function. Activation of KORs has profound effects on emotional states: immediate responses are aversive (Shippenberg and Herz, 1987; Todtenkopf et al., 2004; Knoll et al., 2007), whereas evidence suggests that delayed effects include increased sensitivity to rewarding stimuli (Negus, 2004; McLaughlin et al., 2006). Consistent with this, a Salvia trip often includes a dysphonic component followed by a period of elevated mood after acute intoxication has subsided (Baggott, 2004; Gonzalez et al., 2006). These findings raise the possibility that even occasional use of salvA can induce plasticity within reward circuits, which might facilitate drug abuse and vulnerability to addiction. Chartoff and colleagues have begun to examine the temporal relationship between salvA and reward using the intracranial self-stimulation (ICSS) paradigm, which is sensitive to increases or decreases in reward function in real time. There are biphasic effects: the amount (threshold) of stimulation required to sustain ICSS behavior is increased (reflects decreased reward) immediately after an injection of salvA, but decreased (reflects increased reward) 24 hr later. The neurobiological mechanisms underlying the effects of salvA may be triggered by the inhibitory actions of KORs on DA release (Di Chiara and Imperato, 1988) and involve subsequent neuroadaptations in DA transmission. This proposal is designed to test how salvA modulates brain reward function and sensitivity to the highly addictive drug of abuse, cocaine. Also, the proposal tests how salvA modulates DA signaling at three independent but complementary levels: presynaptic DA release; postsynaptic DA receptor sensitivity; and postsynaptic cAMP-mediated signaling. In preliminary studies, we found that an immediate effect of salvA in the NAc is a decrease, followed 24 hr later by an increase, in the phosphorylation of extracellular signal-related kinase (P-ERK), a substrate for DA receptor-mediated cAMP signaling. In the NAc, ERK can activate CREB, a transcription factor associated with aversive states (Carlezon et al., 1998; Pliakas et al., 2001). Thus, salvA-mediated P-ERK might represent a novel upstream modulator of CREB function in the NAc and mediate the biphasic effects of salvA on reward function.